The integration of retroviral genomes into host chromatin allows HIV to persist within infected cells. The difficulties of lifelong therapy make it imperative to understand the mechanisms of persistent HIV infection, to devise strategies to overcome latent HIV infection. Histone modifying enzymes play a critical role in proviral latency, and histone deacetylase (HDAC) inhibitors induce HIV promoter and viral expression. Drugs of abuse, most notably cocaine, can alter cellular function via epigenetic modification. The durable, epigenetic effect of such environmental influences on memory T cells and persistent HIV infection is unexplored. A more complete understanding of how epigenetics modulate HIV proviral quiescence, and whether latent infection is altered by exposure to cocaine is needed. To achieve this we will comprehensively evaluate the following hypotheses using transformed and primary cell models of latency, and latently infected cells obtained from patients, including patients with a history of cocaine exposure. Specific Aim I: Selected HDACs are specifically recruited to act at the HIV promoter, and targeted HDAC inhibition induces the expression of quiescent proviral HIV: Cofactor complexes recruit HDACs 1, 2, and 3 to act on the HIV LTR, where HDAC isoform occupancy is autoregulated. Blockade of the function of selected HDACs can induce latent proviral expression in model systems, and allow viral recovery from the resting CD4+ T cells of HIV-infected, ART-treated patients. Specific Aim II: Histone deacetylation is an early step in the establishment of restrictive chromatin structures on the silenced LTR: An extensive series of chromatin modifications following histone deacetylation, including histone methylation, results in transition from the inducible to the locked state, decreasing responsiveness of the HIV promoter to single inductive signals. Specific Aim III: Cocaine use will alter the population of latently infected cells, reducing their response to inductive signals: By inducing histone acetylation in resting CD4+ T cells, cocaine exposure will reduce the number of latently infected cells in the inducible state responsive to HDAC inhibitors. Detailed studies of the epigenetics and regulation of proviral quiescence in HIV-infected patients, including the effects of drugs of abuse on latent HIV infection, will enhance our understanding of persistent HIV infection. These studies will guide the development of therapeutic approaches to disrupt persistent proviral infection, and insure that such approaches are applicable to broad populations of patients.